Liver cirrhosis is a major cause of mortality and a common end of various progressive liver diseases. Since the effective treatment is currently limited to liver transplantation, stem cell-based therapy as an alternative has attracted interest due to promising results from preclinical and clinical studies. However, there is still much to be understood regarding the precise mechanisms of action. A number of stem cells from different origins have been employed for hepatic regeneration with different degrees of success. The present review presents a synopsis of stem cell research for the treatment of patients with liver cirrhosis according to the stem cell type. Clinical trials to date are summarized briefly. Finally, issues to be resolved and future perspectives are discussed with regard to clinical applications.
Liver fibrosis results from sustained injury, which can be inflicted by various factors such as viruses, drugs, alcohol, metabolic diseases, and autoimmune attacks . Prolonged exposure to these harmful factors causes hepatocyte apoptosis, inflammatory cell recruitment, endothelial cell impairment, and, lastly, activation of hepatic stellate cells, the major cells involved in liver fibrosis. Liver fibrosis is a kind of scar tissue formation in response to liver damage [2–9]. Histologically, it is caused by an imbalance between extracellular matrix synthesis and degradation [10–12].
Liver cirrhosis is a condition where scar tissue replaces the healthy tissue of the liver and regenerative nodules with surrounding fibrous bands develop as a result of the injury . Cirrhosis is the common end of progressive liver disease of various causes, resulting in chronic liver failure entailing complications such as hepatic encephalopathy, spontaneous bacterial peritonitis, ascites, and esophageal varices . Unfortunately, the majority of cases are usually in an irreversible state when diagnosed. Despite current advancements in its management [15, 16], cirrhosis was the 14th leading cause of death worldwide in 2012 . Orthotopic liver transplantation is known to be the only definite solution to end-stage cirrhosis.
However, several problems preclude the prevalent application of the procedure, including immunological rejection and the scarcity of donor sources .
In fact, the liver has an inherent regenerative capacity to a substantial degree , and, thus, the cessation of those harmful factors may prevent further progression of fibrosis and reverse the situation in some cases . In cases where hepatocyte proliferation is insufficient for recovery from liver injury, bipotent resident liver progenitor cells (LPC) are activated and participate in liver regeneration by differentiating into hepatocytes and biliary epithelial cells [19, 21–23]. However, fibrosis is inevitable when regeneration is exceeded by destruction. Clinical signs of liver failure usually appear after about 80 to 90% of the parenchyma has been destroyed.
Hepatocyte transplantation has been proposed as an alternative approach to transplantation, since hepatocytes have been proven to be strongly associated with liver repair [24–28]. While hepatocyte transplantation is safe in humans, its applicability remains limited due to organ availability, failure of donor engraftment, weak viability in cell culture, and vulnerability to cryopreservation damage [25, 26, 29–32].
Instead of hepatocytes, the transplantation of stem cells has shown therapeutic potential for liver function improvement according to recent experimental studies and human studies [20, 26, 33–40]. Although they remain unclear, the major potential mechanisms have been proposed as a twofold; one is the improvement of the microenvironments through paracrine effects, and the other is the replacement of functional hepatocytes .
To date, several kinds of stem cells have been investigated for their therapeutic feasibility and clinical potential in liver cirrhosis [41–43]. The present article briefly reviews the current literature according to the types of stem cells and discusses the future perspectives of stem cell-based therapy in liver cirrhosis.
- Sources of Stem Cells
Hepatocytes obtained via autopsy of patients who received bone marrow transplantation suggested that they are pluripotent cells in bone marrow [44, 45]. Currently, at least three types of bone marrow-derived cells are known to differentiate into hepatocyte-like cells (HLCs): hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), and endothelial progenitor cells (EPCs), though early infusion trials did not discriminate the origins of those cells from bone marrow-derived stromal cells with some improvement [32, 46–52]. A large number of preclinical studies have proven the feasibility of HSCs, MSCs, and EPCs to restore hepatic function in models of liver injury [53–57]. In addition, other stem cells including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) can also be differentiated into HLCs [58–60]. HLCs can contribute to the remodeling of cirrhotic liver [20, 61–68].